June 21st, 2022

Mayo Clinic Study on Paxlovid Outcomes is Reassuring — but Likely Underestimates Rebound Rate

Filippo Balbi, Testa Anatomica, 1854.

Over at Clinical Infectious Diseases, researchers from the Mayo Clinic published a retrospective analysis of nirmatrelvir/r (Paxlovid) treatment, with a careful review of each patient’s chart.

The goal was to determine the clinical outcomes after the 5-day treatment course, with a focus on the frequency of rebounds — a topic of great clinical interest but with little real-world data with a decent-sized denominator.

The study included 483 patients with at least some risk factors for severe COVID-19 based on the institution’s Monoclonal Antibody Screening Score. Adjudication of eligibility was done centrally through the hospital’s COVID-19 outpatient treatment program. The mean age was 63, and 93% were vaccinated. Patients were given the option of telemedicine follow-up and encouraged to self-report symptoms or other problems; this information and their full electronic medical records were reviewed after the treatment.

Out of this group, 4 (0.8%) clearly experienced clinical rebound — these cases are described. None of the 4 received re-treatment or were hospitalized. Two other patients (neither of them rebounders) did require hospitalization, but the authors note these were unrelated to COVID-19. There were no deaths.

We can be reassured by the information on the low rate of severe outcomes, an outcome mirrored in low hospitalization rates nationally despite lots of ongoing cases. Rates of hospitalization for each COVID-19 case are now extremely low, especially among those vaccinated, and observational studies (peer-reviewed and published and unpublished) suggest that Paxlovid may reduce this risk even further. A large retrospective study from Kaiser Permanente Southern California involving 5,287 patients found similarly  low hospitalization rates.

(Note that these observational studies include patient populations treated with Paxlovid with established risk factors for COVID-19 adverse outcomes — that’s how it’s mostly prescribed under the Emergency Use Authorization (EUA). By contrast, those enrolled in the EPIC-SR study, which was recently stopped due to futility, were “standard risk”. Critically important will be information on baseline characteristics in EPIC-SR.)

For the Mayo study, the authors are to be credited for collecting and reporting the data so quickly, especially at a time when clinicians and patients increasingly observe the rebound phenomenon and wonder what to do about it. The centralized program used for distributing COVID-19 treatments is an additional strength of this report, as it allowed participants the opportunity to self-report progression of symptoms, and upfront ensured that all who were treated met the criteria for high risk based on the EUA.

The big limitation of this Mayo study, however, is that it’s retrospective. As a result, I strongly suspect the 0.8% rate of rebound substantially underestimates the true incidence. Pfizer reported rebounds in 2% of study participants in the prospective EPIC-HR trial, a rate more than twice as high. Based on anecdotal experience — there’s lots of Paxlovid treatment out there! — I would not be surprised if it’s at least 10 times this high, or in the 5-10% range.

What still remains unknown, frustratingly, is whether treatment with subsequent rebound reduces — or paradoxically increases — the total amount of time that people are contagious, or, if the total time is the same, does it just delay the time that a person can confidently say that they’re in the clear?

Why is this important? I’ve had people tell me that they don’t want to take the drug because they’ve heard it might lengthen the time they’re contagious. And I’ve had other patients who experienced rebound express regret on having taken the drug — even though we have no idea whether they would have tested positive for a prolonged period even without the treatment.

Let’s hope further data from prospective studies give us some answers — in particular, the placebo-controlled trials, either Pfizer’s two studies or the large PANORAMIC trial done in the United Kingdom.

In the meantime, I’m still advising people at higher risk for COVID-19 adverse outcomes — even if vaccinated — to be treated with Paxlovid, uncertainties about the above issues notwithstanding.

11 Responses to “Mayo Clinic Study on Paxlovid Outcomes is Reassuring — but Likely Underestimates Rebound Rate”

  1. Alexander Evens says:

    This was just released. MMWR reports a study from Kaiser here in CA. See link…


    Their main findings included…

    “from patients aged ≥12 years in a large integrated health care system who received Paxlovid treatment during December 2021–May 2022, hospitalizations or ED encounters for COVID-19–related illness during the 5–15 days after Paxlovid dispensation occurred among <1% of all patients. The rarity of these outcomes is consistent with evidence from recent case reports and large observational studies, which found that symptoms experienced by patients with COVID-19 rebound after treatment with Paxlovid are milder than those experienced during the primary infection and are unlikely to lead to hospitalization"

  2. David Krohn says:

    How strong is the contraindication for use of Paxlovid in patients presenting taking either Dilantin or Phenobarbital or both?

  3. i_e_rabinovitz says:

    Dr. Sax: Can you please provide a short list in rank order those risk factors you consider dispositive for Paxlovid treatment? I frequently hear the public-relations organs mention that “older persons” are considered “at greater risk”. I always wish to shout back, “older than whom?” But somehow there is no answer forthcoming. The culture of euphemism is such that they are afraid to be specific for fear of offending the fearsome cohort of those both aged and contentious? Jesting aside — seriously now — is a 50 year old with no other chronic conditions considered an “older person” and at risk? I=A 55 year-old? A 60 year-old? Many Thanks -IER

    • S. W. says:

      Hi IER,

      The best way to prevent severe disease or death is staying up to date on your Covid-19 vaccines. For your age group, that means getting a second booster.

      The NIH Covid-19 Treatment Guidelines, the IDSA Guidelines, and the text of the emergency use authorization itself all refer to a CDC website with information about risk factors for progression to severe disease: https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions.html.

      The page notes that “age remains the strongest risk factor for severe COVID-19 outcomes.” There is a summary graphic from a large study showing that someone who is 50–64 years old is 4.3 times as likely to die from Covid as someone who is 18–39 years old. The risk ratio was adjusted for comorbidities and other important factors. The unadjusted risk ratio was even higher.

      Supply of Paxlovid and other therapeutics is plentiful. But when supply is limited, the NIH Treatment Guidelines recommend that vaccinated people who are at least 65 years old and without other risk factors should be prioritized in the last tier. Right now, it’s better to err on the side of giving treatment than not giving treatment.

  4. Marilyn Wilking says:

    Why 5 day treatment? Would 7 days or 10 days as uniform treatment prevent relapse? This is an infectious disease; length of treatment generally relates to “successful” treatment.

  5. Bertha Flores says:

    Does the medicine work paxlovid if your vaccinated an booster.should you take it if you get covid 19.what are the factors in taking this medicine.does it work.

  6. John A Fleming says:

    Not related to the study but timeliness in getting this medication to patients also seems to be an issue. Since the reccomendation is to start the course in first 5 days. I’m hearing it’s getting better but for me it was too late once the pharmacies in my area had it in stock.

  7. Susan Levenstein says:

    I’m sure you’ve by now seen https://www.medrxiv.org/content/10.1101/2022.06.21.22276724v1 which confirms your suspicions: a symptomatic rebound rate of nearly 6%, with 0.8% going on to require hospitalization.


    Interesting situation.
    Recently took Paxlovid for 5 days after testing +ve for Covid . relatively mild URT symptoms .I think I got better quickly although I did feel ” dark” when taking the drug . 5 days was long enough .
    Now a few weeks later I have a cough with mildly coloured sputum and nasal stuffiness.
    I am beginning to think this could be Covid related although testing negative.
    I am an N of one but agree that documenting the use of Paxlovid and sequelae is worthy of
    I have had four shots the last being 5 days before testing +ve

  9. Karla Brandenburg RN Retired says:

    I’m a 72 yr old control Asthmatic for past 4 yrs and took Paxlovid within 24 hr after testing positive. Took the traditional 5 day course and experience low BP and feeling extreme tiredness and persistent productive light gray/yellowish sputum plus nasal congestion. I have continued to test positive post Paxlovid and on the fifth (5) day after completion of the Paxlovid besides having the above symptoms, I lost my sense of smell n taste.
    I have remained on all my Asthma medication (Theophyl, Spirva, Dulera, Dupixent injection Bi-monthly,) with no Asthma Flair-ups or hospitalization. It is important to include the fact I’ve been on Valacyslovir/Lotemax 0.5% eye drops for 23 years. My initial vaccination series was Moderna with subsequent Moderna two booster thereafter. To date, I remained COVID positive with thrust at the base of my tongue slight sore throat, BP still low 97/73 -103/76-HR 77-90, no fever/chills.
    My question Sir, is how long will it take to regain my sense of taste/smell? I’ve been in quarantine since June 19, 2022 n still remain COVID positive.

  10. John Angotti, MD says:

    Haven’t seen much on the effect of Paxlovid on the incidence of Long Covid. Any research coming?

HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

Contributing Editor

NEJM Journal Watch
Infectious Diseases

Biography | Disclosures | Summaries

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